rs267607170

chr3-10149814-A-Gchr3-10149814-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):c.491A>G(p.Gln164Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q164H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.26

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10149815-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 456566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 3-10149814-A-G is Pathogenic according to our data. Variant chr3-10149814-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.491A>G	p.Gln164Arg	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3	c.368A>G	p.Gln123Arg	missense_variant	2/2
VHL	NM_001354723.2	c.*45A>G		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.820A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.491A>G	p.Gln164Arg	missense_variant	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2021	Variant summary: VHL c.491A>G (p.Gln164Arg) results in a conservative amino acid change located in the alpha domain, which is known to interact with Elongin C (IPR024048). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes (gnomAD). c.491A>G has been reported in the literature in multiple patients/families affected with Von Hippel-Lindau Syndrome (VHL) or with VHL-related tumors, including at least one individual with de novo occurrence (e.g. Chen_1995, Zbar_1996, Webster_1999, Mattocks_2000, Ong_2007, Sovinz_2010, de Cubas_2013, Neumann_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that while this variant didn't affect elongin B and C binding in an in vitro peptide-binding assay, the Q164R mutant full-length protein had reduced binding ability to elongin B and Cul2 in transiently transfected renal carcinoma cells (Ohh_1999). In addition, another study also reported that though the variant protein had retained elongin C binding, the variant significantly reduced the intracellular stability of VHL protein (Park_2015). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln164 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12807974, 19215943, 22517557, 24102379; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 2238). This missense change has been observed in individual(s) with von Hippel-Lindau disease (PMID: 7728151, 17024664, 20583150). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 164 of the VHL protein (p.Gln164Arg). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2020

The p.Q164R (also known as c.491A>G) pathogenic mutation, located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 491. The glutamine at codon 164 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in patients with clinical diagnoses of von Hippel-Lindau syndrome (VHL), or VHL related tumors (Chen F et al. Hum. Mutat. 1995;5:66-75; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Sovinz P et al. Am. J. Med. Genet. A. 2010 Jul;152A:1752-5; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Fallon SC et al. J. Pediatr. Surg. 2013 Jun;48:1422-5; Krauss T et al. Endocr. Relat. Cancer. 2018 Sep;25:783-793). In one case, this variant was identified in a 2-year-old child with pheochromocytoma. It was found to be de novo in the patient's father, who also had pheochromocytoma, retinal angioma, and an adrenal adenoma (Sovinz P et al. Am. J. Med. Genet. A. 2010 Jul;152A:1752-5). In vitro functional studies do not show specific impaired functions, including elongin C binding, however, one study showed a shorter protein half-life than wild type leading the authors to speculate that the protein may be unstable (Ohh M et al. J. Clin. Invest. 1999 Dec;104:1583-91; Maynard MA et al. J. Biol. Chem. 2003 Mar;278:11032-40; Park KS et al. BMC Cancer. 2015 Oct;15:800). Another alteration at the same codon, p.Q164H (c.492G>C) , has been reported in a family diagnosed with PGLs and PCCs (Bauters C et al. J. Med. Genet. 2003 Jun;40:e75), and internal structural analysis indicated the alteration disrupts the fold of the elongin binding domain of VHL (Ambry internal data; Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12). In addition, the p.Q164R variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.83
Sift4G	Benign	0.16	T;D
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.93		Gain of MoRF binding (P = 0.0098);.;
MVP		1.0
MPC		1.1
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607170; hg19: chr3-10191498; COSMIC: COSV56546711;